Gender differences in genotypic distribution of endothelin-1 gene and endothelin receptor A gene in pulmonary hypertension associated with rheumatic mitral valve disease

Introduction: The female gender is a risk factor for idiopathic pulmonary arterial hypertension. However, it is unknown whether females with rheumatic mitral valve disease are more predisposed to develop pulmonary hypertension compared to males. Aim: We aimed to investigate whether there was a difference in genotypic distribution of endothelin-1 (ET-1) and endothelin receptor A (ETA) genes between female and male patients of pulmonary hypertension associated with rheumatic mitral valve disease (PH-MVD). Methods: We compared prevalence of ET-1 gene (Lys198Asn) and ETA gene (His323His) polymorphisms according to gender in 123 PH-MVD subjects and 123 healthy controls. Results: The presence of mutant Asn/Asn and either mutant Asn/Asn or heterozygous Lys/Asn genotypes of Lys198Asn polymorphism when compared to Lys/Lys in females showed significant association with higher risk (odds ratio [OR] 4.5; p ¼0.007 and OR 2.39; p ¼0.02, respectively). The presence of heterozygous C/T and either mutant T/T or heterozygous C/T genotypes of His323His polymorphism when compared to wild C/C genotype in females showed a significant association with higher risk (OR 1.96; p ¼0.047 and OR 2.26; p ¼0.01, respectively). No significant difference was seen in genotypic frequencies in males between PH-MVD subjects and controls. Logistic regression analysis showed that mutant genotype Asn/Asn (p ¼0.007) and heterozygous genotype Lys/Asn of Lys198Asn polymorphism (p ¼0.018) were independent predictors of development of PH in females.

Protective effect of ETaR siRNA on renal ischemia-reperfusion injury in rats by changing the immuno-microenvironment of kidney / 中华器官移植杂志

Objective To explore the protective effect of ETaR siRNA on renal ischemia reperfusion injury (IRI) by changing the immuno-microenvironment in rats .Methods A total of 40 male Sprague-Dawley (SD) rats were randomized into four groups of sham ,IR ,negative siRNA and ETaR siRNA .A renal IRI model was generated by clamping left renal artery .ETaR siRNA was delivered into kidney through renal vein by a retrograde 'hydrodynamic' injection .Blood samples were collected for detecting renal function and kidney tissue harvested for Hematoxylin & Eosin (HE) staining , TdT-mediated dUTP Nick-End Labeling (TUNEL) staining ,polymerase chain reaction (PCR) and Western blot at 48 h post-reperfusion .Results Serum creatinine ,blood urea nitrogen and renal apoptotic cells increased and renal tissue was injured after IR . The changes were inhibited by ETaR siRNA . PCR showed that ETaR siRNA treatment significantly down-regulated the expressions of inflammatory factors TNF-α , IFN-γ and IL-6 and transcription factor NF-κB induced by IR .Conclusions ETaR siRNA can effectively improve the immunomicroenvironment and thereby alleviate renal ischemia reperfusion injury .

Effect of Ambrisentan Therapy on the Expression of Endothelin Receptor, Endothelial Nitric Oxide Synthase and NADPH Oxidase 4 in Monocrotaline-induced Pulmonary Arterial Hypertension Rat Model

BACKGROUND AND OBJECTIVES: Elevated endothelin (ET)-1 level is strongly correlated with the pathogenesis of pulmonary arterial hypertension (PAH). Expression level of nicotinamide adenine dinucleotide phosphate oxidase (NOX) 4 is increased in the PAH patients. Ambrisentan, a selective endothelin receptor A (ERA) antagonist, is widely used in PAH therapy. The current study was undertaken to evaluate the effects of ambrisentan treatment in the monocrotaline (MCT)-induced PAH rat model. METHODS: Rats were categorized into control group (C), monocrotaline group (M) and ambrisentan group (Am). The M and Am were subcutaneously injected 60 mg/kg MCT at day 0, and in Am, ambrisentan was orally administered the day after MCT injection for 4 weeks. The right ventricle (RV) pressure was measured and pathological changes of the lung tissues were observed by Victoria blue staining. Protein expressions of ET-1, ERA, endothelial nitric oxide synthase (eNOS) and NOX4 were confirmed by western blot analysis. RESULTS: Ambrisentan treatment resulted in a recovery of the body weight and RV/left ventricle+septum at week 4. The RV pressure was lowered at weeks 2 and 4 after ambrisentan administration. Medial wall thickening of pulmonary arterioles and the number of intra-acinar arteries were also attenuated by ambrisentan at week 4. Protein expression levels of ET-1 and eNOS were recovered at weeks 2 and 4, and ERA levels recovered at week 4. CONCLUSIONS: Ambrisentan administration resulted in the recovery of ET-1, ERA and eNOS protein expression levels in the PAH model. However, the expression level of NOX4 remained unaffected after ambrisentan treatment.

Mechanism of endothelin-1 mediated the cyclic intermittent hypoxia on carotid body plasticity in rats / 解剖学报

Objective To investigate the potential molecular mechanism of endothelin-1 (ET-1) involved in cyclic intermittent hypoxia (CIH) induced carotid body chemoreceptor plasticity. Methods (1) Animal experiment: 32 male Sprague-Dawley (SD) rats were randomly divided into two groups: Control group (Con) and CIH group (CIH), 16 rats per group. After 21 days of CIH exposure, each group (Con and CIH) was subdivided into 2 groups: Lail vein injection of ET-1 (1 x 10~6 mol/kg body weight) or same volume of saline according to the above dose. After 30 minutes of injection, carotid bodies were collected and Western blotting was used to detect the change of tested proteins. (2) Carotid body organ culture: Rat carotid bodies were isolated and cultured in the incubator, and treated with ET-i (lxlO"4 mol/L) for different times (0 minute, 10 minutes, 60 minutes). The effect of ET-1 on the phosphorylation of p38 mitogen-activated protein l kinase (p38 MAPK) was detected by Western blotting. Results (1) CIH increased the protein level of endothelin receptor A (ET-A)and ET-B in the rat carotid body. (2) Compared with the ET-1 injected Con group, phosphorylated protein kinase A (p-PKA), p-p38 MAPK, phosphorylated Ca2;/calmodulin-dependent protein kinase D (p-CaMK II) and phosphorylated cAMP response element-binding protein (p-CREB) and RhoA protein level were significantly up-regulated in ET-1 injected CIH rats. (3) Application of ET-1 to organ cultured carotid bodies resulted in the elevation of p-p38 MAPK in a time-dependent manner. Conclusion ET-1 may regulate CIH-induced carotid body chemoreflex plasticity through PKA/p38 MAPK/CaMK II/CREIJ and IthoA signaling.

Selective inhibition of endothelin receptor A improves white matter le-sions in hypertensive rats / 中国病理生理杂志

AIM:To observe whether selective inhibition of endothelin receptor A(ETRA)improves white matter lesions(WMLs),and explore the mechanism.METHODS:Sprague-Dawley rats(n=33)were randomly divided into sham operation group(n=9),treatment group[stroke-prone renovascular hypertensive rats-modified 2 vessel occlu-sion(RHRSP-modified 2VO)+ambrisentan(n=12)]and placebo group[RHRSP-modified 2VO +vehicle(n =12)].Drug and vehicle administration was performed from 17th to 20th week and monitoring of systolic arterial pressure was performed weekly.Morris water maze test was conducted to evaluate the function of cognition.The protein levels of en-dothelin-1(ET-1)in the cortex,corpus callosum and caudate putamen were quantitatively analyzed respectively.The se-verity of WMLs and the relationship between ET-1 and vessels were observed by the method of histopathology.RESULTS:The difference of systolic arterial pressure between treatment group and placebo group was not significant.The animals in treatment group exhibited shorter escape latency(P<0.05),more times of crossing platform(P<0.05), lower level of ET-1 in corpus callosum and caudate putamen(P<0.05),respectively,improved WMLs severity(P<0.05)and lower binding level of ET-1 to vessels compared with the placebo group.CONCLUSION: Selective inhibition of endothelin receptor A improves the severity of WMLs and ameliorates the cognitive function.

Association between Polymorphism of Endothelin Receptor Type A and Delayed Cerebral Vasospasm in Patients with Aneurysmal Subarachnoid Hemorrhage / 现代检验医学杂志

Objective To investigate the genetic association between endothelin receptor type A(EDNRA)gene polymor-phism and delayed cerebral vasospasm(DCVS)in patients with aneurysmal subarachnoid hemorrhage(aSAH).Methods 133 aSAH patients from January 2015 to January 2017 were recruited to participate in the study.According to whether com-bined with DCVS,they were divided into the DCVS group(78 cases)and the control group(55 cases).Genotype was deter-mined by polymerase chain reaction-restriction fragment length polymorphism combined with DNA direct sequencing tech-nique for the polymorphism of the EDNRA gene.Results Samples of DCVS group and control group both were consistent with Hardy-Weinberg's law of inheritance(χ2=0.295,P=0.863;χ2=0.652,P=0.722).There were significant differ-ences of EDNRA gene rs5335 polymorphism between DCVS group and control group,under allele model(χ2=4.213,P=0.040)and the dominant model(χ2=4.790,P=0.029).However,there was no difference of EDNRA gene polymorphism between DCVS group and control group under recessive model(χ2=1.299,P=0.254).Multivariate Logistic regression a-nalysis showed that allele C was protective factor of DCVS for aSAH patients(OR=0.572,95%CI 0.401~0.872,P=0.021).Conclusion For aSAH patients,EDNRA gene rs5335 polymorphism may closely related to DCVS.

Effect of sitaxsentan on renal microcirculation in beagle dogs undergoing cardiopulmonary bypass:mornitoring using ultrasound microbubble angiography / 中华麻醉学杂志

Objective To evaluate the effect of sitaxsentan on renal microcirculation in beagle dogs undergoing cardiopulmonary bypass(CPB)when ultrasound microbubble angiography was used to monitor renal microcirculation.Methods Eighteen male Beagle dogs,weighing 10-15kg,aged 2-4 yr,were allocated into 3 groups(n=6 each)using a random number table:sham operation group(Sham group),CPB group and sitaxsentan group(S group).Sitaxsentan 0.7 mg/kg was infused over 30min starting from 1 h before CPB in group S.Before CPB(T1),at 1 h of CPB(T2),at the end of CPB(T3)and at 2h after the end of CPB(T4),the time-intensity curve of renal parenchyma perfusion was obtained using ultrasound microbubble angiography,and quantitative parameters including the slope rate of ascending curve(A),area under curve(AUC),derived peak intensity(DPI)and time to peak(TTP)were fitted.Results Compared with Sham group,the value of A was significantly decreased at T2-4,AUC and TTP were increased at T3,4,DPI was decreased at T4 in renal cortex and medulla in CPB group,and the value of A was significantly decreased and TTP was increased at T2-4,AUC was increased at T3,4(P0.05).Compared with CPB group,the value of A was significantly increased and AUC and TTP were decreased at T3,4 in renal cortex and medulla(P0.05).Conclusion Sitaxsentan can improve renal microcirculation in beagle dogs undergoing CPB.

Plasmatic Biochemical Variables Associated with Polymorphisms in the Endothelin-1 and Endothelin-1 Receptor a Genes in Hypertensive Patients: Pilot Study.

Aims: Endothelin-1 (ET-1) is a potent vasoconstrictive peptide, and its activity is mediated by the type A receptor (EDNRA). This action may play a significant role in the etiology of hypertension. There are different works that shows an association between certain polymorphisms of endothelin axis and clinical phenotype of hypertension. We describe the genetic variability +138/ex1 insertion/deletion (I/D) adenosine (A) in the ET-1 gene and polymorphism thymidine/cytosine (T/C) His323His in the EDNRA gene associated at the clinical variability in hypertensive patients. Study Design: Observational, transversal and analytical study. Place and Duration of Study: Hypertension Service at the Internal Medicine Department of Córdoba Hospital, and Biochemical and Molecular Biology Department in School of Medicine, National University of Cordoba, Argentine. Patients considered hypertensive between April 2009 and April 2010. Methodology: Were assessed 136 patients serum lipid profiles, renal and hepatic functions and were taken Thoracic X-rays, electrocardiograms, and echocardiographs. DNA extracted from circulating leukocyte were used to analyze the polymorphisms of genes by PCR-RFLP. Results: For the polymorphisms of Receptor A from Endothelin -1 studied the presence of cytosine homozygous genotype was less frequent in males (P = .02). For both genders, the same genotype was associated to low plasma alkaline phosphatase activity and cholesterol levels. The presence of thymidine nucleotide allele correlated with plasma alkaline phosphatase activity and cholesterol levels. The Thymidine allele correlated with the degree of cardiovascular compromise (r = 0.54, P= .002). For the genetic variant in the ET-1 gene, the homozygous adenine deletion was associated to normal plasma levels of glutamate/pyruvate transaminase enzyme activity, uric acid concentration, cholesterol, and Low Density Lipoprotein in hypertensive subjects without clinical risk. Conclusion: We observed a gender-specific protective effect for EDNRA gene variations, the subjects that carried the TT genotype presented more aggressive symptomatology. These results show an association between plasmatic biochemical parameters, the clinical condition, and polymorphisms in the endothelin axis genes.

The role of unbalanced expression of endothelin receptor (ETA/ETB)in basilar artery vasospasm after subarachnoid hemorrhage in rats / 西安交通大学学报(医学版)

Objective To investigate the mechanism of unbalanced expressions of endothelin receptors (ETA/ETB )in cerebral vasospasm (CVS)after subarachnoid hemorrhage (SAH).Methods The rat CVS models were established by injecting autologous blood into the cisterna magna the second time.Basilar artery morphology was observed under light microscope and immunofluorescence staining was conducted to dynamically detect ETA/ETB receptor expression.Results The cross-sectional area of the basilar artery in the SAH model group decreased at 2 d to 3 d,and then gradually returned to normal.ETA receptor expression in endothelial cells of the basilar artery increased at 2 d after SAH,peaked at 3 d and remained increased till 14 d.ETB receptor expression increased significantly in endothelial cells at 3 d,peaked at 7 d and remained the same level till 14 d.Conclusion The results suggest that ETA/ETB receptors play an important role in cerebral vasospasm after SAH.The specific expression differences of ETB receptor subtypes in the brain vascular layers need further study.

Recent Advances in the Management of Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening and progressive disease characterized by pulmonary vascular remodeling that leads to increased pulmonary vascular resistance and pulmonary arterial pressure, most often resulting in right-sided heart failure. Originally considered to be a disorder of vasoconstriction and vasodilatation, it has become clear that the predominant characteristic of PAH is abnormal cellular proliferation leading to progressive obliteration of the pulmonary vasculature. Current PAH-specific therapies target one of three major pathways involved in development and progression of PAH: 1) The endothelin pathway targeted by the endothelin receptor antagonists (ERAs); 2) the prostacyclin pathway, targeted by prostacyclin analogs and 3) the nitric oxide (NO) pathway, targeted by the phosphodiesterase type 5 (PDE-5) inhibitors.

TOF treatment for early postoperative use of endothelin receptor antagonist for the BNP impact study / 中华胸心血管外科杂志

Objective To determine the brain natriuretic peptide(BNP) levels and the effects of endothelin receptor antagonist(ERA) on BNP levels in patients with tetralogy of Fallot(TOF) recently surgical repaired.Methods During January 2010 to January 2012,32 cases of TOF after surgical repaired in hospital were selected.There are 20 males and 12 females,Aged 4 years to 18 years [mean age (7.64 ± 3.75) years] in age.All patients underwent enhanced CT to evaluate the pulmonary vessels and left ventricular before surgery arrangements.As the surgeries done,the patients were grouped randomly as either A or B.All 14 patients in group A started to follow the recommended dosage of bosentan within 3 days after surgery.Meanwhile,all 18 in group B had not taken bosentan or any other ERAs since the surgeries.Both group was evaluated and examined with echocardiography and blood test at the 10th day after surgery.Results None of the patients died within 10 days after surgery.BNP levels of group A was significantly lower than of group B.Inotropic score of group A was markedly lower,too.However,although group A showed mildly advantages in tricuspid regurgitation,pulmonary regurgitation,ratio of RV/LV end-systolic dimension and liver functions,there was no statistically significant difference.Conclusion For patients with tetralogy of Fallot,early use of ERAs after surgical repaired could reduce the use of inotropic agents and significantly decrease the BNP levels when discharged.

Benign Prostatic Hyperplasia: Current and Future Therapeutics.

Benign prostatic hyperplasia (BPH) is one of the most common diseases of old-aged men affecting >90% of men in their 70s and 80s. Although the exact cause is not known, most people agree that dihydrotestosterone plays a strong role in pathogenesis. BPH can be a progressive disease. Severe BPH can cause serious problems including renal insufficiency. Surprisingly the risk factors for BPH are found to be the same as for cardiovascular diseases. Management of BPH has changed significantly in the last decade. α-blockers and 5α-reductase inhibitors are the most commonly used drugs. A number of other drugs belonging to newer groups like phosphodiesterase inhibitors, hexokinase inhibitors like lonidamine, antagonists of endothelin, vanilloid and purine receptors and modulators of JM-27 expression are also showing promise. These are in different stages of clinical trials. The surgical counterpart of treatment has also witnessed recent advancements. Newer techniques like potassium-titanylphosphate (KTP) laser and photo selective vaporization of prostate have been shown to have nearly equal efficacy as that of transurethral resection of prostate (TURP) with less side effects.

Antagonistas de los receptores de la endotelina para la hipertensión arterial pulmonar / Endothelin receptor antagonists for pulmonary arterial hypertension / Antagonistas dos receptores de endotelina para a hipertensão arterial pulmonar

La hipertensión arterial pulmonar (HAP) es consecuencia de una alteración aguda o crónica de la vasculatura pulmonar, que se caracteriza por el aumento de la presión arterial pulmonar como consecuencia del aumento de la resistencia vascular pulmonar. La fisiopatología de la HAP se caracteriza por la vasoconstricción pulmonar vascular, la proliferación de células musculares lisas, y la trombosis. Estos cambios son el resultado de un desequilibrio entre agentes vasodilatadores (prostaciclina, óxido nítrico, péptido intestinal vaso activo) y vasoconstrictores (tromboxano A2, endotelina, serotonina), los inhibidores de factores de crecimiento y mitógenos, y factores antitrombóticos y protrombóticos. Los recientes avances en el tratamiento están dirigidos a restablecer el equilibrio entre estos sistemas. Los antagonistas de los receptores de endotelina (bosentán, ambrisentán), inhibidores de la fosfodiesterasa tipo 5 (sildenafilo, tadalafilo), y prostaciclina (epoprostenol, iloprost, treprostinil, beraprost) representan las diferentes clases de medicamentos que se utilizan actualmente en monoterapia y en combinación para el tratamiento de la HAP. El propósito de esta revisión es proporcionar al lector una actualización del tratamiento de la HAP con antagonistas de los receptores de la endotelina.

Pulmonary arterial hypertension (PAH) is a consequence of acute or chronic disorder of the pulmonary vasculature, which is characterized by increased pulmonary artery pressure as a result of increased pulmonary vascular resistance. The pathophysiology of PAH is characterized by pulmonary vascular vasoconstriction, smooth muscle cell proliferation, and thrombosis. These changes are a result of an imbalance between vasodilators (prostacyclin, nitric oxide, vasoactive intestinal peptide) and vasoconstrictors (thromboxane A2, endothelin, serotonin), growth inhibitors and mitogenic factors, and antithrombotic and prothrombotic factors. Recent advances in treatment are directed at restoring the balance between these systems. Endothelin receptor antagonists (bosentan, ambrisentan), phosphodiesterase type 5 inhibitors (sildenafil, tadalafil), and prostacylin (epoprostenol, iloprost, treprostinil, beraprost) represent the different classes of medications that are currently used in monotherapy and in combination to treat PAH. The purpose of this review is to provide the reader with an update on the treatment of PAH with antagonists of endothelin receptors.

A hipertensão arterial pulmonar (HAP) é uma consequência da doença aguda ou crônica da vasculatura pulmonar, o que é caracterizado pelo aumento da pressão da artéria pulmonar, como um resultado da resistência vascular pulmonar aumentada. A fisiopatologia de HAP é caracterizada pela vasoconstrição pulmonar vascular, proliferação de células de músculo liso, e trombose. Estas alterações são um resultado de um desequilíbrio entre os vasodilatadores (prostaciclina, o óxido nítrico, o péptido intestinal vasoativo) e vasoconstritores (tromboxano A2, endotelina, serotonina), e inibidores de crescimento de fatores miogênicos, e fatores antitrombóticos e pró-trombóticos. Avanços recentes no tratamento são dirigidos para o restabelecimento do equilíbrio entre estes sistemas. Antagonistas do receptor da endotelina (bosentan, ambrisentan), inibidores da fosfodiesterasa tipo 5 (sildenafilo, tadalafilo) e prostaciclina (epoprostenol, iloprost, treprostinil, beraprost) representam as diferentes classes de medicamentos que são usados atualmente em monoterapia e em combinação para tratar HAP. O objetivo desta revisão é fornecer ao leitor uma atualização sobre o tratamento da HAP com os antagonistas dos receptores de endotelina.

Expression Changes of Endothelin-1, Endothelin Receptor A and B in the Cochlea after Noise Exposure / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: There are several evidences of reduced cochlea blood flow after noise exposure in the cochlea. However, the pathophysiology of blood flow change is still obscure, and endothelins, proteins that constrict blood vessels and play a key role in vascular homeostasis using its receptors may have importance in this respect. In this study, we investigated the expression changes of endothelin-1 (ET-1), endothelin receptor A (ETAR) and B (ETBR) according to auditory threshold change after noise exposure. MATERIALS AND METHOD: Mice were exposed to different noise to generate transient (group 2) and permanent threshold shift (group 3), respectively. Auditory threshold shifts were evaluated with auditory brainstem response and expression changes of ET-1, ETAR and ETBR after noise exposure were evaluated by immunohistochemistry and real time RT-PCR. RESULTS: After noise exposure, the increased ET-1, ETAR and ETBR immunoreactivities were observe in stria vascularis, spiral ligament and spiral ganglion neuron. ET-1 mRNA expressions increased after noise exposure in both group 2 and group 3 compared to those of the control group. At 2 weeks after noise exposure, however, the ET-1 mRNA expressions in group 3 increased compared to that of the control but decreased compared to that of group 2. On the other hand, ETAR mRNA expression increased at 2 weeks after noise exposure in both groups, just after noise exposure in group 2 and at 2 weeks after noise exposure in group 3. CONCLUSION: These results suggest that expression changes of ET-1, ETAR and ETBR might be associated with hearing threshold shift and recovery after noise exposure in the cochlea.

Expression of endothelins and endothelin receptors in retina of diabetic rats / 第二军医大学学报

Objective To investigate the expression of endothelin-1 (ET-1), ET-2, ET-3, endothelin receptor A (ETRA), ETRB and endothelin coverting enzyme (ECE) in the retinas of 8-week-old diabetic SD rats. Methods The retinal gene expression profiles of healthy and 8-week-old diabetic rats were constructed with restriction fragment differential display polymerase chained reaction (RFDD-PCR), and the differential expression of ET-1, ET-2, ET-3, ETRA, ETRB and ECE was verified using semi-quantitative RT-PCR and Western blotting analysis. Results The results of RFDD-PCR showed that the expression of ET-1, ET-2, ET-3, ETRA, ETRB and ECE was up-regulated in diabetic retina. The results of semi-quantitative RT-PCR and Western blotting analysis showed that the expression levels of the six genes and proteins (relative D ratio) in diabetic group were significantly higher than those in the normal retinas (P<0. 05 and P<0. 01, respectively). Conclusion The expression of ET-1, ET-2, ET-3, ETRA, ETRB and ECE is up-regulated in diabetic retina, suggesting that the six genes may be involved in the pathgenesis of diabetic retina.

The Hirschsprung's-multiple endocrine neoplasia connection

The risk of patients with Hirschsprung's disease later developing multiple endocrine neoplasia remains a matter of concern. The multiple endocrine neoplasia 2-Hirschsprung's disease association has been shown to cosegregate in Hirschsprung's disease patients with both short- and long-segment aganglionosis, although patients with long-segment aganglionosis a to carry the greatest risk. The Hirschsprung's disease-medullary thyroid carcinoma relationship also appears to be bi-directional, and activation or suppression of the rearranged during transfection gene appeared to vary over succeeding generations within the same family. Rearranged during transfection gene variations are associated with both conditions. The cosegregation of Hirschsprung's disease and multiple endocrine neoplasia 2 is particularly interesting as it involves both "switch off" and "switch on" of the rearranged during transfection proto-oncogene in the same patient. This cosegregation mostly relates to the cysteine-rich area on RET620 (the "Janus gene"). The mechanism whereby rearranged during transfection influences gene activation in multiple endocrine neoplasia 2 is complex, but genetic variations impair the rearranged during transfection tyrosine kinase response to tyrosine kinase activation, thus appearing to dictate downstream signaling cascade responses. Better understanding of the RET-620 relationship allows for a more cost-effective method of identifying those at risk by focusing rearranged during transfection gene testing to this specific area as a "hot spot". The clinical awareness of possible medullary thyroid carcinoma has led to timely intervention and early treatment of this chemo- and radioresistant tumor with poor prognosis. Establishment of "risk" by genetic testing has become a classic model of molecular medicine being integrated into patient care and offering rearranged during transfection directed prophylactic surgical management. In addition, novel approaches to treatment based on this genetic knowledge have already shown early promise in randomized clinical trials.

CPU0213, a novel endothelin type A and type B receptor antagonist, protects against myocardial ischemia/reperfusion injury in rats

The efficacy of endothelin receptor antagonists in protecting against myocardial ischemia/reperfusion (I/R) injury is controversial, and the mechanisms remain unclear. The aim of this study was to investigate the effects of CPU0123, a novel endothelin type A and type B receptor antagonist, on myocardial I/R injury and to explore the mechanisms involved. Male Sprague-Dawley rats weighing 200-250 g were randomized to three groups (6-7 per group): group 1, Sham; group 2, I/R + vehicle. Rats were subjected to in vivo myocardial I/R injury by ligation of the left anterior descending coronary artery and 0.5 percent sodium carboxymethyl cellulose (1 mL/kg) was injected intraperitoneally immediately prior to coronary occlusion. Group 3, I/R + CPU0213. Rats were subjected to identical surgical procedures and CPU0213 (30 mg/kg) was injected intraperitoneally immediately prior to coronary occlusion. Infarct size, cardiac function and biochemical changes were measured. CPU0213 pretreatment reduced infarct size as a percentage of the ischemic area by 44.5 percent (I/R + vehicle: 61.3 ± 3.2 vs I/R + CPU0213: 34.0 ± 5.5 percent, P < 0.05) and improved ejection fraction by 17.2 percent (I/R + vehicle: 58.4 ± 2.8 vs I/R + CPU0213: 68.5 ± 2.2 percent, P < 0.05) compared to vehicle-treated animals. This protection was associated with inhibition of myocardial inflammation and oxidative stress. Moreover, reduction in Akt (protein kinase B) and endothelial nitric oxide synthase (eNOS) phosphorylation induced by myocardial I/R injury was limited by CPU0213 (P < 0.05). These data suggest that CPU0123, a non-selective antagonist, has protective effects against myocardial I/R injury in rats, which may be related to the Akt/eNOS pathway.

Pharmacotherapy for pulmonary arterial hypertension

Although pulmonary arterial hypertension (PAH) is an orphan disease with high mortality and for which there is no cure, current treatment have led to considerable gains in the outcomes of these patients. Oral anticoagulation is proposed for most patients; diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia. High doses of calcium-channel blockers are indicated only in the minority of patients who respond to acute vasoreactivity testing. Nonresponders to acute vaoreactivity testing or who remain in World Health Organization (WHO) functional class III, should be considered candidates for treatment with either an oral phophodiesterase-5 inhibitor or an oral endothelin-receptor antagonist. Continuous intravenous administration of epoprostenol remains the treatment of choice in WHO functional class IV patients. Combination therapy is recommended for patients treated with PAH monotherapy who remain in WHO functional class III. The pharmacologic management of PAH is rapidly evolving as newer therapeutic targets that stabilize or reverse pulmonary vascular disease and as clinical practice pattern shift in favor of earlier diagnosis and aggressive treatment. Questions about preferred first-line therapy and when to institute combination therapies remain. Future drug development targeting other molecular pathways of PAH is essential for definitively improving patient survival. The search for novel treatment continues, with promising new concepts arising from a better understanding of the pathobiology of PAH.

Changes in Endothelin Receptor Type B and Neuronal Nitric Oxide Synthase in Puromycin Aminonucleoside-Induced Nephrotic Syndrome

The collecting duct endothelin (ET) system, which involves ET-1 and its two receptors, may play a role in the regulation of renal sodium in association with the nitric oxide synthase (NOS) system. We determined whether sodium retention is associated with changes in the endothelin and NOS systems at different stages (i.e., a sodium retaining stage and a compensatory stage) of nephrotic syndromes. On day 7 after puromycin aminonucleoside (PAN) injection, urinary sodium excretion was decreased, ascites had developed, and there was a positive sodium balance. ET-1 mRNA expression was increased in the inner medulla of the kidney, whereas protein expression of ET receptor type B (ET(B)R) was unchanged. The expression of neuronal NOS (nNOS) was decreased in the inner medulla. On day 14, urinary sodium excretion was unchanged compared with controls. The expression of ET(B)R increased, while nNOS expression in the inner medulla was comparable to controls. These findings suggest that decreased nNOS plays a role in the development of sodium retention in the nephrotic syndrome. Recovery of nNOS and increased renal ET(B)R synthesis may promote sodium excretion in later stages of the nephrotic syndrome (on day 14).

The mechanism and pulmonary-protective effects of endothelin-1 receptor antagonist in chronic obstructive pulmonary diseases rat model / 中华内科杂志

Objective To investigate whether the endothelin (ET) receptor antagonists have protective role in the development of emphysema. Methods Spragne-Dawley rats (n = 24) were divided into four groups: control group, cigarette smoke extract (CSE) group, BQ123 group and Bosentan group. CSE was injected intraperitoneally once a week for three weeks and BQ123 and Bosentan were administered daily for the same duration. TdT-mediated dUTP nick end labeling(TUNEL) was performed to observe the deoxyribonucleic acid (DNA) damaged cells and the expression of caspase-3 was determined by immunohistochemistry and Western blot. Matrix metalloproteinase-2 (MMP-2) and MMP-9 activities were investigated by gelatin zymography and tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) concentrations were measured by enzyme linked immunosorbent assay (ELISA). Results We confirmed the emphysematous destruction in the lungs of experimental rats induced by the intraperitoneal injection of CSE within 3 weeks. The mean lining inteval (MLI) and damage index (DI) were significantly increased in the CSE group compared with control group. However, the MLI and DI were significantly decreased in the BQI23 and bosentan groups compared with CSE rats (P < 0. 01, respectively). The TUNEL-positive cells were markedly distributed in the peribronchioles, intra-alveoli, and septal areas of the emphysematous lungs in CSE rats comparing with the lungs of control rats. The apoptosis index (AI) was significantly higher in CSE group than control group. And the AI was significantly reduced in BQ123 group and bosentan group compared with that in CSE group. The caspase-3 positive ceils were markedly distributed in the emphysematous lungs of CSE group comparing with the stained cells in the lungs of control rats. These positive cells were apparently reduced in the BQ123 and bosentan groups compared with the stained cells in CSE group. Comparing with the control group, expression of caspase-3 was prominently enhanced in CSE groups, but both BQ123 and bosentan treatments markedly inhabited the increases of the cleaved caspase-3 protein levels in rats injected with CSE. Rats injected with CSE showed increased MMP-2 and MMP-9 activities in their lung tissue homogenates and MMP-2 and MMP-9 activities were reduced significantly in both BQ123 and bosentan groups. The levels of TNFα and IL-1β were significantly increased in the CSE group in comparison to those in controls. BQ123 and bosentan significantly prevented the increases of the levels of TNFα and IL-1β in lungs of rats with injection of CSE. Condusions ET-1 may have an important role in the pathological process of emphysema and ET receptor antagonists protect against the development of emphysema probably by decelerating apoptosis, inhibiting proteolytic enzyme activity and reducing inflammatory cytokine levels.